Oxamic acid derivatives

ABSTRACT

Anti-allergic agents of aromatic oxamic acid derivation present the following formula: ##STR1## in which A is a member selected from the group consisting of α-naphthyl, β-napthtyl, phenyl, 2,6-di-chlorophenyl, and substituted phenyl moieties containing from one to three substituents in any of the 2,3,4 and 5 positions of the phenyl ring, independently selected from the group consisting of lower alkyl, lower alkylthio, lower alkylsulfinyl, lower alkoxy, hydroxy (lower)alkoxy, 2-(oxalyloxy) ethoxy, benzyloxy, N-mono- and di-lower alkylamino(lower)alkoxy, halo, sulfamyl, polyhalo(lower)alkyl, carbamyl, N-lower alkylcarbamyl, nitro, mono and di lower alkylamino, carboxy, lower alkylcarbonyl, carb(lower)alkoxy, phenoxy(lower)alkoxy, and oxalamidophenoxy radicals; 
     and pharmaceutically acceptable salts thereof.

RELATED APPLICATIONS

This application is a continuation-in-part of Ser. No. 834,614, filedSept. 19, 1977 now U.S. Pat. No. 4,154,961, which application is acontinuation-in-part of Ser. No. 669,565, filed Mar. 23, 1976 now U.S.Pat. No. 4,069,343, which application is a continuation-in-part of Ser.No. 542,465, filed Jan. 20, 1975, now U.S. Pat. No. 3,966,965, whichapplication in turn is a continuation-in-part of Ser. No. 344,466, filedMar. 23, 1973, now abandoned.

BACKGROUND OF THE INVENTION

Atopic immediate sensitivity is the chief manifestation found in animalssuffering from bronchial asthma, seasonal pollinosis (e.g. hay fever),allergic rhinitis, urticaria, allergic conjunctivitis, food allergiesand anaphylactoid reactions. The substances most frequently responsiblefor clinically manifest sensitivities are plant pollen, animal feathersand danders, dust, milk and wheat, whether inhaled or ingested.

Atopic hypersensitivity is found in man, dog and other animals. Itsoccurrance is exceptionally found in the lower animals.

The presence of antibodies associated with atopic hypersensitivityreactions in the host serum is established by the passive sensitizationof the skin of a normal recipient, after injection of serum from asensitized host into a skin site followed by injection of antigen intothe same area 24 hours later, resulting in a local hive. This iscommonly referred to as the Prausnitz-Kustner (P-K) reaction.

The antibody associated with atopic hypersensitivity possessesdistinctive features in that it does not in all forms precipitate withits antigen, fails to pass the placenta from mother to fetus, hasspecial affinity for the skin, frequently lacks specificity torward anindividual antigenic factor and is usually labile at about 56° C. aftertwo hours.

The homocytotropic antibody found in or induced in the rat is related infunction and reaction to immunoglobulin E (reagin or IgE) found in thehuman. The correlation between homocytotropic antibody in the rat andIgE in the human has been established through the common effectsobtained from chemical reactions, immunological reactions and drugresponses in the two species hosting those antibodies. In the human,reagin is the antibody responsible for atopic immediate hypersensitivereactions. In the rat, the homocytotropic antibody is responsible foratopic immediate hypersensitive reactions.

In theory, reagin, influences the cell membrane of a mast cell byreacting with an antigen, to initiate the reaction(s) within the mastcell which ultimately releases a mediator such as Bradykinin, SRS-A(slow reacting substance-A), histamine and other unknown substances. Themediator effects a change in surrounding cell wall permeabilitypermitting a rapid change in flow or exudance of mediator(s) from thecells, resulting in an allergic attack symptom. The various methodscommonly employed to relieve the symptoms of allergic attack, none ofwhich are considered to be quite acceptable, are to (1) avoid attack bythe antigen, (2) block the production of antibody with animmunosuppressant, (3) block the action of the mediators on the cellunder attack by administration of anti-histaminics,anti-5-hydroxy-tryptamines(5-HT) or anti-inflammatories, or (4)stimulate the cell under attack to negate the action of the mediatorthrough the action of bronchodilators such as Isuprel® or a Xanthine.

The only compound known to date to operate as an anti-allergic byblocking reactions(s) within the mast cells, thereby preventing theproduction and release of mediators, is disodium cromoglycate (INTAL®).

Derivatives of oxamic acids have been employed in the past asintermediates for polymer formation and as tools for chemical research.Each of the known oxamic acid derivatives included as part of the newuse aspect of this application is accompanied with a reference citationin the working examples, infra.

DESCRIPTION OF THE INVENTION

In accordance with this invention, there is provided a process forpreventing the release of pharmacological mediators from an immediatehypersensitivity reaction between reaginic type antibodies and anantigen, thereby preventing the symptoms manifest in bronchial asthma,seasonal pollinosis, allergic rhinitis, urticaria, allergicconjunctivities, food allergy and anaphylactoid reactions of asensitized animal, which comprises prophylactically administering tosaid animal an effective amount of a compound of the formula: ##STR2##in which A is a member selected from the group consisting of αnaphthyl,β-naphthyl, phenyl, 2,6-dichlorophenyl, and substituted phenyl moietiescontaining from one to three substituents in any of the 2,3,4 and 5positions of the phenyl ring, independently selected from the groupconsisting of lower alkyl, lower alkylthio, lower alkylsulfinyl, loweralkoxy, hydroxy(lower)alkoxy, 2-(oxalyloxy) ethoxy, benzyloxy, N-mono-and di-lower alkylaminoalkoxy, halo, sulfamyl, polyhalo(lower)-alkyl,carbamyl, N-lower alkylcarbamyl, nitro, mono- and di-lower alkylamino,carboxy, lower alkylcarbonyl, carb(lower)alkoxy, phenoxy(lower)alkoxyand oxalamidophenoxy radicals;

and pharmaceutically acceptable salts thereof.

The preferred method aspect of this invention comprises administering toa sensitized animal a compound which, in minimal dosage quantity, willsuppress the allergic response to a degree of or in excess of 75 percentof the characteristic wheal size of sensitized skin tissue, whichcompounds present the structural formula: ##STR3## in which A isα-naphthyl, β-naphthyl, phenyl, 2,6-dichlorophenyl or a substitutedphenyl moiety containing from one to three substituents, in any of the2,3,4 and 5 positions of the phenyl ring, independently selected fromthe group consisting of lower alkyl, fluoro, lower alkoxy,hydroxy-(lower)alkoxy, N-mono- or di(lower)alkylamino(lower)-alkoxy,(lower)alkylthio, carbamoyl, carb(lower alkoxy oxalyloxy) ethoxy,trifluoromethyl, nitro, and phenoxy(lower)alkoxy;

and pharmaceutically acceptable salts thereof.

The novel aromatic oxamic acid derivatives form an additional aspect ofthis invention.

The aromatic oxamic acid derivatives present the formula: ##STR4## inwhich A is a number selected from the group consisting of3-fluorophenyl, 4-carbamylphenyl, 2-nitro-4-trifluoromethylphenyl,4-nitro-3-trifluoromethylphenyl, 5-chloro-2-sulfamoylphenyl and ##STR5##wherein R¹ is a member selected from the group consisting of hydroxyl,lower alkyl, lower alkoxy, lower alkylamino and amino radicals;

R² is a member selected from the group consisting of hydrogen, loweralkoxy, di(lower)alkylamino(lower)-alkoxy, hydroxy(lower)alkoxy,phenoxy(lower)alkoxy, 2-(oxalyloxy)ethoxy and lower alkylthio radicals;with the proviso that when R¹ is hydroxy or lower alkoxy, R² is otherthan hydrogen;

R³ is a member selected from the group consisting of hydrogen, loweralkyl, and lower alkoxy radicals;

R⁴ is a member selected from the group consisting of -H, lower alkyl andlower alkoxy with the proviso that one of R², R³ and R⁴ must be otherthan hydrogen.

The term "lower" used throughout this application to modify alkyl,alkoxy, and the like, is intended to embrace univalent aliphatichydrocarbon radicals containing from 1 to 6 carbon atoms. The term"halo" is used to embrace chlorine, bromine, iodine and fluorine.

Each of the carboxylic acids constituting this invention has beendemonstrated in the form of their simple esters to relieve atopicallergic manifestations, when administered intraperitoneally tosensitized rats. Several of the compounds tested were found to beeffective anti-allergy agents when administered orally to the sensitizedanimals.

The technique employed to establish the anti-allergic activity of thedisclosed compounds is reported in Immunology, vol. 16, pp. 749-760(1969) and involves four male Charles River rats (200-250 grams bodyweight) per group to provide a control, a host for administration of astandard anti-allergic compound (disodium cromoglycate) and animals forthe test compound. The rats were injected intracutaneously on theirshaved backs with sera from rats immunized with egg albumin andpertussis vaccine. Twenty-four hours after the initial injections, thetest compound is administered intraperitoneally or orally at a dosagelevel of 200 milligrams per kilogram host body weight. Five minuteslater one milliliter of a 0.5 percent solution of Evans blue dye and 8milligrams of egg albumin is injected intravenously. After fortyminutes, the animal is sacrificed and the bleb size on its back ismeasured. The mean bleb size for the animals administered the testcompound is calculated and the percent inhibition is determined bycomparison with the control animal. A representative number of thecompounds were tested at dosage levels considerably below 200 milligramsper kilogram host body weight to establish the activity of the compoundsat minimal concentrations as low as 3 milligrams per kilogram host bodyweight.

Although the mechanism by which the compounds of this invention functionis not absolutely known, applicants have found that the compounds ofthis invention, in a manner believed to be similar to the function ofINTAl^(R), block reaction(s) in the mast cell leading to the productionand release of mediators.

The compounds of this invention permit the occurrence of anon-productive antigen-antibody interaction. They effectively block theIgE type reaction and have little or no effect on the otherimmunoglobulins such as IgG, IgM, IgA and IgD.

The compounds of this invention have no pharmacological response patternsimilar to known anti-allergics in that they have no anti-hypertensiveactivity (no cardiovascular effect, etc.), they have no analgesicactivity, they have no central nervous system activity, they have noimmunosuppressive activity, they have no activity against histamine,serotonin, Bradykinin, etc. and they have no endocrinological activity.

In sum, the compounds of this invention block the release of mediatorscommonly resulting from the antigen-antibody reaction as exemplified ina passive cutaneous anaphylaxis test (PCA) using rat homocytotropicantibody--a known correlate of human reaginic antibody.

By analogy to disodium cromoglycate and its activity correlation betweenstandard test animals, domestic animals and man, the compounds of thisinvention have been established as anti-allergic agents suitable for thesame uses at analogous doses and through the same routes ofadministration as INTAL®. Several of the compounds of this inventionhave been found to be effective anti-allergic agents when administeredorally. The orally active compounds of special interest are the methyl,ethyl and i-propyl oxanilate, ethyl 3'-methyloxanilate, ethyl4'-methoxyoxanilate, ethyl and secondary butyl2'-carbamoyl-3'-methoxyoxanilate, ethyl4'-nitro-3'-(trifluoromethyl)oxanilate and ethyl 1-naphthyloxamate,2'-carbamoyl-3'-(2-hydroxypropoxy)-oxanilic acid ethyl ester,(2-carbamoyl-3, 5-dimethoxyphenyl)-oxamic acid ethyl ester, oxalic acid(2-[2-aminocarbonyl-3-ethoxy carbonylcarbonylaminophenoxy]ethyl)ethylester, [2-carbamoyl-3(2-hydroxyethoxy)phenyl]oxamic acid ethyl ester,3-benzyloxy-2-carbamoylphenyl)oxamic acid ethyl ester,(4-dimethylaminophenyl)-oxamic acid ethyl ester,[2-(aminocarbonyl)-3-(dimethylamino)phenyl]oxamic acid ethyl ester,[2-carbamoyl-3-(methylthio)-phenyl]oxamic acid ethyl ester and[(2-aminocarbonyl-3 -methylsulfinylphenyl)amino]oxo acetic acid ethylester.

Thus, there is provided herewith a method for suppressing allergicmanifestations of atopic immediate sensitivity in warm-blooded human andnon-human animals, the latter including domesticated animals such as themouse, rat, hamster, gerbil, dog, cat, sheep, goat, horse, cow, and thelike, by administering an effective amount of one or more of thecompounds disclosed in this application by oral, topical, parenteral,rectal, vaginal or inhalation routes. Since the compounds of thisinvention afford no pharmacological response pattern similar to orantagonistic to common anti-allergics, they may be administered inconjunction with known compounds effecting anti-histaminic,anti-hypertensive, analgesic, central nervous system depressant,immunosuppressive, anti-serotonin, anti-Bradykinin or endocrinologicalresponses. In addition, those conventional adjuvants known to the artmay be combined with the anti-allergics of this invention to providecompositions and solutions for administrative purposes, although it isconsidered desirable and feasible to employ the anti-allergics as neator pure compounds without additives other than for purposes of providingsuitable pharmaceutical solution or liquid or vapor suspensions.

The effective dose range in test animals has been established to be fromabout 1.5 milligrams per kilogram to a dosage resulting in 100 percentprevention of allergic responses at 5 milligrams per kilogram host bodyweight upon administration intraperitoneally. The oral dose range liesfrom about 1.5 milligrams per kilogram to 90 percent prevention ofallergic response at 200 milligrams per kilogram host body weight. As aninhalant the dose is from that of INTAL®, (about 20 milligrams) to1/20th that quantity administered as needed prior to attack. Thus thedosage contemplated for human use based upon the potency of thecompounds administered lies from about 100 milligrams to 1 gram,preferably 250 milligrams to about 750 milligrams in unit dosage form tobe administered when necessary and to the degree of the desiredresponse, in single or plural doses under the guidance of a physician.

The compounds of this invention have not been found to be toxic to mice,the standard experimental animal in toxicity studies of this nature, atany administered dose up to and in excess of two grams per kilogram hostbody weight. No toxic level has been found in other standard testanimals. The anti-allergic compounds of this invention appear to be freefrom side effects common to other anti-allergics such as sedation,dizziness, depression, etc.

The aromatic oxamic acid derivatives are generally prepared by reactionof an appropriately substituted aromatic amino or heterocyclic aminowith an appropriately substituted oxalylchloride in the presence of anacid acceptor, such as pyridine, at ambient temperature. The techniqueemployed in the preparation of each of the specifically disclosedcompounds is presented in the following working examples either indetail or by citation of the appropriate literature, the latter beingincorporated herein by reference. Throughout the following Examples,reference is made to CA (Chemical Abstracts), Zh. Obshch. Khim (TheJournal of General Chemistry-Russia), Rec. Trav. Chim (Recueil desTravaux Chimique des Pays-Bas-Netherlands), Heilbron (Dictionary ofOrganic Compounds), Ber. Deut. Chem. (Berichte der deutschen chemischenGesellschaft), J. Org. Chem. (Journal of Organic Chemistry), J.A.C.S.(Journal of the American Chemical Society) and Farmaco, Ed. Sci. (IlFarmaco Scientifica Edition-Italy).

In the working examples, the number following the entitled compoundrefers to intraperitoneal/oral activity data obtained at a dosage levelof 200 milligrams per kilogram host body weight, unless otherwiseindicated. The activity data represents the percent inhibition of themean bleb size of sensitized rats administered the named compound inaccordance with the test procedure presented, supra. The oral data isrepresentatively presented for those compounds exhibiting inhibition offifty percent or more of the weal size in the test animals at 200milligrams per kilogram host body weight unless otherwise indicated.

In the following examples, the various esters produced are readilyconverted to the corresponding free carboxylic acid by conventionaltechniques well known to the art; Example 26 illustrating one suchprocess. The free carboxylic acids, active in their own right asanti-allergic agents, also represent intermediates for the production ofesters, where the alcoholic moiety is to be tailored for lipidesolubility, for the production of pharmaceutically acceptable salts suchas the alkali metal and ammonium salts or an amine salt which is readilyderived from such known pharmaceutically acceptable amines asdiethylamine, di-(hydroxy ethyl)amine, N,N'-dibenzylethylenediamine, andthe like, or for the production of an amide. Likewise, the expression"pharmaceutically acceptable salt" is intended to embrace thosenon-toxic acid addition salts which may be formed with either organic orinorganic acids such as hydrochloric, hydrobromic, sulfuric, phosphoric,methane sulfonic, nitric, p-toluene sulfonic, acetic, citric, maleic,succinic acid and the like.

EXAMPLE 1 Oxanilic acid ethyl ester. 100/64

The title compound is known in the literature: G. Tiere, Rec. Trav.Chim., 52, 420-4 (1933). It is crystallized from ethanol, m.p. 64°-67°C.

EXAMPLE 2 Oxanilic acid methyl ester. 100/52

The title compound is known in the literature:

Heilbron Dict. of Org. Cpds., IV, p. 32. (1965). It is crystallized fromdiethyl ether, m.p. 113°-116° C.

EXAMPLE 3 Oxanilic acid n-propyl ester. 82

The title compound is known in the literature: Heilbron Dict. of Org.Cpds., Vol. IV, p. 32, (1965). It is crystallized from diethyl ether,m.p. 90°-92° C.

EXAMPLE 4 Oxanilic acid i-propyl ester. 100/60

The title compound is known in the literature: Heilbron Dict. of Org.Cpds., Vol. IV, p. 32 (1965). It is crystallized from pentane, m.p.51°-53° C.

EXAMPLE 5 Oxanilic acid phenyl ester. 59

The title compound is known in the literature; R. Stolle et al., Ber.Deut. Chem., 54B, 1213-20 (1921). It is crystallized from ethanol, m.p.136°-139° C.

EXAMPLE 6 2'-Carboxyoxanilic acid 1-ethyl ester. 50

The title compound is known in the literature: J.A.C.S. 32, 119 (1910).It is crystallized from toluene, m.p. 182°-183° C.

EXAMPLE 7 2'-Carbamoyloxyanilic acid ethyl ester. 90

The title comound is known in the literature: B. R. Baker et al., J.Org. Chem., 27, 4672 (1962). It is crystallized from ethanol, m.p.160°-161° C.

EXAMPLE 8 2'-Methyloxanilic acid ethyl ester. 75

The title compound is known in the literature: P. E. Todesco et al.,C.A. 61:419f. It is a liquid, b.p. 126° C./0.05 mm. Hg.

EXAMPLE 9 2'-Methoxyoxanilic acid ethyl ester. 100

The title compound is known in the literature: C.A.:61 (4192). It iscrystallized from benzene, m.p. 81°-85° C.

EXAMPLE 10 3'-Methoxyoxanilic acid ethyl ester. 38

The title compound is known in the literature: P. A. Petyunin et. al.,ZH. Obshch. Khim., 21, 1859-61 (1951). It is crystallized frommethanol-water, m.p. 95°-98° C.

EXAMPLE 11 3'Trifluoromethyloxanilic acid ethyl ester. 64

The title compound is known in the literature: A. Buruffini, et. al.,Farmaco, Ed. Sci., 22 (9), 717-34 (1967). It is crystallized fromethanol, m.p. 120°-123° C.

EXAMPLE 12 3'-Fluorooxanilic acid ethyl ester. 78

m-Fluoroaniline (5.55 g., 0.05 mole) is condensed with 6.16 ml. (0.055mole) of ethyl oxalyl chloride in 100 ml. dichloromethane in thepresence of pyridine at about 10° C. with stirring, giving 9.26 g. ofthe title compound, m.p. 85°-89° C. after crystallization from ethanol.

Elemental Analysis for C₁₀ H₁₀ FNO₃ : Calc'd: C, 57.0; H, 4.78; N, 6.64:Found: C, 56.45; H, 4.87; N, 6.61.

EXAMPLE 13 3'-Methyloxanilic acid ethyl ester. 85

The title compound is known in the literature: P. A. Petyunin et. al.,Zh. Obshch. Khim., 24, 1078-82 (1954). It is crystallized frombenzene-hexane, m.p. 56°-60° C.

EXAMPLE 14 4'-Carbamoyloxanilic acid ethyl ester. 55

p-Aminobenzamide (4.08 g., 0.03 mole) is condensed with 3.7 ml. (0.033mole) of ethyl oxalyl chloride in a manner similar to example 12, giving2.85 g. of the title compound, m.p. 259°-264° C. (dec.), aftercrystallization from N,N-dimethylformamide.

Elemental Analysis for C₁₁ H₁₂ N₂ O₄ : Calc'd: C, 55.93; H, 5.12; N,11.86: Found: C, 56.01; H, 5.24; N, 11.92.

EXAMPLE 15 4'-Methoxyoxanilic acid ethyl ether. 75/76

The title compound is known in the literature: A. Piutti et. al., Br.Deut. Chem., 31, 330-336 (1898). It is crystallized from ethanol, m.p.100°-104° C.

EXAMPLE 16

4'-Nitrooxanilic acid ethyl ester. 75

The title compound is known in the literature: G. Tierie, Rec. Trav.Chim., 52, 420-4 (1933). It is crystallized from acetic acid, m.p.169°-172° C.

EXAMPLE 17 4'-Methyloxanilic acid ethyl ester. 100

The title compound is known in the literature: C.A. 61 (4192). It iscrystallized from benzene-hexane, m.p. 65°-67° C.

EXAMPLE 18 2'-Carbamoyl-3'-methoxyoxanilic acid ethyl ester. 100/94

6-Amino-o-anisamide (8.75 g., 0.0527 mole) is condensed with 6.2 ml.(0.0554 mole) of ethyl oxalyl chloride in a manner similar to example12, giving 8.35 g. of the title compound, m.p. 170°-173° C., aftercrystallization from ethanol.

Elemental Analysis for C₁₂ H₁₄ N₂ O₅ : Calc'd: C, 54.13; H, 5.30; N,10.52: Found: C, 54.36; H, 5.20; N, 10.66.

EXAMPLE 19 2-Carboxy-3'-methoxyoxanilic acid ethyl ester. 54

6-Amino-o-anisic acid (1.671 g., 0.01 mole) is condensed with 1.23 ml.(0.011 mole) of ethyl oxalyl chloride in a manner similar to example 12,giving 1 g. of the title compound, m.p. 142°-144° C., aftercrystallization from ethanol.

Elemental Analysis for C₁₂ H₁₃ NO₆ : Calc'd: C, 53,93; H, 4.90; N, 5.24;Found: C, 54.21; H, 4.99; N, 5.32.

EXAMPLE 20 2'-Carbamoyl-3'-chlorooxanilic acid ethyl ester. 25

2-Amino-6-chlorobenzamide (4.26 g., 0.025 mole) is condensed with 3.1ml. (0.0275 mole) of ethyl oxalyl chloride in a manner similar toexample 12, giving 5.28 g. of the title compound, m.p. 190°-193° C.,after crystallization from ethanol.

Elemental Analysis for C₁₁ H₁₁ CLN₂ O₄ : Calc'd: C, 48.8; H, 4.10; N,10.35: Found: C, 49.08; H, 4.05; N, 10.72.

EXAMPLE 21 2'-Carboxy-3'-methoxyoxanilic acid 1-ethyl 2'-methyl ester.78

Methyl 6-methoxyanthranilic acid (3.62 g., 0.02 mole) is condensed with2.46 ml. (0.022 mole) of ethyl oxalyl chloride in a manner similar toexample 12, giving 3.51 g. of the title compound, m.p. 96°-99° C. aftercrystallization from ethanol.

Elemental Analysis for C₁₃ H₁₅ NO₆ : Calc'd: C, 55.51; H, 5.38; N, 4.98:Found: C, 55.56; H, 5.43; N, 5.18.

EXAMPLE 22 2'-Carbamoyl-3'-(2-phenoxyethoxy)oxanilic acid ethyl ester.75

2-Phenoxyethanol (4.15 ml., 0.033 mole) is added to dimethylsulfoxylsodium prepared from 1.39 g. of 57 percent sodium hydride and 40 ml.dimethylsulfoxide, giving a mixture of the solid salt of the alcoholafter about 20 minutes. This mixture is added to a solution of 5.8 g.(0.030 mole) 2,6-dinitrobenzonitrile in 20 ml. of dimethylsulfoxide at30°-40° C., and the resulting purple solution is stirred over night atroom temperature. The solvent is removed at 70° C. on a rotaryevaporator, and the residue is triturated with water. A solid isfiltered off and it is dissolved in ethyl acetate. The ethyl acetatesolution is washed twice with H₂ O, brine, and dried with calciumsulfate. Evaporation of the ethyl acetate gives 8.5 g. of2-nitro-6(2-phenoxyethoxy)benzonitrile, which is crystallized from 200ml. ethyl alcohol, giving 6 g., m.p. 129°-137.5° C.

The crystallized 2-nitro-6-(2-phenoxyethoxy)benzonitrile (5.82 g.,0.0205 mole) is stirred in 116 ml. absolute ethanol at 50° C. and 3.62ml. (0.0615 mole) 85 percent hydrazine hydrate is added, followed bysmall scoops of Raney nickel. The temperature is kept at 50°-60° C.while the Raney nickel is added, and after gas evolution and theexotherm ceases, the mixture is filtered through diatomaceous earth. Thefilter cake is washed with hot ethanol and the filtrate is concentrated,giving 2.804 g. of 2-amino-6-(2-phenoxyethoxy)benzamide m.p. 127°-130°C.

Elemental Analysis for C₁₅ H₁₆ N₂ O₃ : Calc'd: C, 66.16; H, 5.92; N,10.29: Found: C, 66.71; H, 6.36; N, 10.13.

2-Amino-6-(2-phenoxyethoxy)benzamide (2.8 g., 0.0103 mole) is condensedwith 1.26 ml. (0.0113 mole) of ethyl oxalyl chloride in a manner similarto example 12, giving 1.62 g. of the title compound, m.p. 142°-145° C.,after crystallization from ethanol.

Elemental Analysis for C₁₉ H₂₀ N₂ O₆ : Calc'd: C, 61.28; H, 5.41; N,7.52: Found: C, 61.14; H, 5.57; N, 7.50.

EXAMPLE 23 2'-Carbamoyl-3'-methoxyoxanilic acid methyl ester. 96

6-Amino-o-anisamide (4.98 g., 0.03 mole) is condensed with 3.04 ml.(0.033 mole) of methyl oxalyl chloride in a manner similar to example12, giving 4.24 g. of the title compound, m.p. 195°-198° C., aftercrystallization from methanol.

Elemental Analysis for C₁₁ H₁₂ N₂ O₅ : Calc'd: C, 52.28; H, 4.80; N,11.11: Found: C, 52.30; H, 4.94; H, 11.40.

EXAMPLE 24 2'-Carbamoyl-3'-methoxyoxanilic acid n-propyl ester. 96

6-Amino-o-anisamide (4.98 g., 0.03 mole) is condensed with 4.25 ml.(0.033 mole) of n-propyl oxalyl chloride in a manner similar to example12, giving 4.81 g. of the title compound, m.p. 158°-161° C., aftercrystallization from acetonitrile.

Elemental Analysis for C₁₃ H₁₆ N₂ O₅ : Calc'd: C, 55.71; H, 5.75; N,10.00: Found: C, 55.92; H, 5.93; N, 10.34.

EXAMPLE 25 2'-Carbamoyl-3'-methoxyoxanilic acid isopropyl ester. 57

6-Amino-o-anisamide (4.98 g., 0.03 mole) is condensed with 4.25 ml.(0.033 mole) of isopropyl oxalyl chloride in a manner similar to example12, giving 4.74 g. of the title compound, m.p. 128°-132° C., aftercrystallization from benzene.

Elemental Analysis for C₁₃ H₁₆ N₂ O₅ : Calc'd: C, 55.71; H, 5.75; N,10.00: Found: C, 55.66; H, 5.93; N, 10.38.

EXAMPLE 26 2'-Carbamoyl-3'-methoxyoxanilic acid. 48

2'-Carbamoyl-3'-methoxyoxanilic acid ethyl ester (1.33 g., 0.005 mole)is stirred in 50 ml. water, and 5.0 ml. of N NaOH is slowly added,giving a solution. After 1/2 hour the solution is filtered, and thefiltrate is acidified to pH 2 with N HCl, giving 0.71 g. of the titlecompound, m.p. 214°-215° C., after crystallization from ethanol.

Elemental Analysis for C₁₀ H₁₀ O₅ N₂ : Calc'd: C, 50.42; H, 4.23; N,11.76: Found: C, 50.60; H, 4.35; N, 11.80.

EXAMPLE 27 N-(2-Carbamoyl-3-methoxyphenyl)oxamide. 26

2'-Carbamoyl-3'-methoxyoxanilic acid ethyl ester (5.0 g., 0.0188 mole)is added to 50 ml. of ethanol saturated with ammonia at 0°-5° C., andthe mixture is stirred in an ice-bath for 2 hours, then filtered. Thecake is washed with ethanol, giving 1.41 g. of the title compound, m.p.252°-255° C., after crystallization from water.

Elemental Analysis for C₁₀ H₁₁ N₃ O₂ : Calc'd: C, 50.63; H, 4.67; N,17.72: Found: C, 50,45; H, 4.70; N, 17.65.

EXAMPLE 28 2'-Carboxy-4'-methoxyoxanilic acid ethyl ester. 61

5-Methoxyanthranilic acid (1.67 g., 0.01 mole) is condensed with 1.23ml. (0.011 mole) of ethyl oxalyl chloride in a manner similar to example12, giving 1.32 g., of the title compound, m.p. 238°-243° C., aftercrystallization from ethanol.

Elemental Analysis for C₁₂ H₁₃ NO₆ : Calc'd: C, 53.93; H, 4.90; N, 5.24:Found: C, 53.99; H, 4.93; N, 4.99.

EXAMPLE 29 2'-Carbamoyl-4'-chlorooxanilic acid ethyl ester. 58

2-Amino-5-chlorobenzamide (3.41 g., 0.02 mole) is condensed with 2.46ml. (0.022 mole) of ethyl oxalyl chloride in a manner similar to example12, giving 4.57 g. of the title compound, m.p. 204°-210° C., aftercrystallization from acetonitrile.

Elemental Analysis for C₁₁ H₁₁ ClN₂ O₄ : Calc'd: C, 48.8; H, 4.10; N,10.35; Cl, 13.10: Found: C, 48.65; H, 3.98; N, 10.26; Cl, 12.84.

EXAMPLE 30 2'-Carbamoyl-4'-nitrooxanilic acid ethyl ester. 59

2-Amino-5-nitrobenzamide (5.43 g., 0.03 mole) is condensed with 3.7 ml.(0.033 mole) of ethyl oxalyl chloride in a manner similar to example 12,giving 6.54 g. of the title compound, m.p. 206°-209° C., aftercrystallization from ethanol.

Elemental Analysis for C₁₁ H₁₁ N₃ O₆ : Calc'd: C, 46.98; H, 3.94; N,14.94: Found: C, 46,68; H, 3.96; N, 15.12.

EXAMPLE 31 4'-Methoxy-2'-nitrooxanilic acid ethyl ester. 84

The title compound is known in the literature: Zh. Obshch. Khim. 1,2471-7 (1937). It is crystallized from ethanol, m.p. 154°-160° C.

EXAMPLE 32 2'-Nitro-4'-(trifluoromethyl)oxanilic acid ethyl ester. 29

4-Amino-4-nitrobenzotrifluoride (3.21 g., 0.03 mole) is condensed with3.7 ml. (0.033 mole) of ethyl oxalyl chloride in a manner similar toexample 12, giving 3.84 g. of the title compound, m.p. 186°-188° C.,after crystallization from ethanol.

Elemental Analysis for C₁₂ H₁₄ N₂ O₅ : Calculated: C, 43.1; H, 2.96; N,9.16: Found: C, 42.97; H, 3.02; N, 9.28.

EXAMPLE 33 2'-Carbamoyl-5'-methoxyoxanilic acid ethyl ester. 91

2'-Nitro-4-methoxybenzonitrile (12.8 g) is reduced in a manner similarto example 22, giving 9.0 g. of 2-amino-p-anisamide, m.p. 152°-156° C.,after crystallization from water.

Elemental Analysis for C₈ H₁₀ N₂ O₂ : Calc'd: C, 57.82; H, 6.07; N,16.86: Found: C, 58.60; H, 5.76; N, 16.65.

2-Amino-p-anisamide (4.99 g., 0.03 mole) is condensed with 3.68 ml.(0.033 mole) of ethyl oxalyl chloride in a manner similar to example 12,giving 3.84 g. of the title compound, m.p. 186°-188° C., aftercrystallization from ethanol.

Elemental Analysis for C₁₂ H₁₄ N₂ O₅ : Calc'd: C, 54.13; H, 5.34; N,10.52: Found: C, 54.29; H, 5.50; N, 10.89.

EXAMPLE 34 5'-Chloro-2'-sulfamoyloxanilic acid ethyl ester. 70

2-Amino-4-chlorobenzenesulfonamide (4.13 g., 0.02 mole) is condensedwith 2.46 ml. (0.022 mole) of ethyl oxalyl chloride in a manner similarto example 12, giving 3.04 g. of the title compound, m.p. 183°-187° C.,after crystallization from ethanol.

Elemental Analysis for C₁₀ H₁₁ CLN₂ O₅ S: Calc'd: C, 39.2; H, 3.65; N,9.14; S, 10.45: Found: C, 38.95; H, 3.65; N, 9.14; S, 10.86.

EXAMPLE 35 2'-Carboxy-4'-methoxyoxanilic acid 1-ethyl 2'-methyl ester.58

6-Amino-m-anisic acid methyl ester (4.7 g., 0.0283 mole) is condensedwith 3.48 ml. (0.311 mole) of ethyl oxalyl chloride in a manner similarto example 12, giving 5.27 g. of the title compound, m.p. 129°-133° C.,after crystallization from ethanol.

Elemental Analysis for C₁₃ H₁₅ NO₆ : Calc'd: C, 55.51; H, 5.38; N, 4.98:Found: C, 55.72; H, 5.38; N, 5.37.

EXAMPLE 36 2',6'-Dichlorooxanilic acid ethyl ester. 100

The title compound is known in the literature: C.A.: 60 (1621a). It iscrystallized from diethyl ether, m.p. 128°-130° C.

EXAMPLE 37 4'-Nitro-3'-(trifluoromethyl)oxanilic acid ethyl ester.100/73

5-Amino-2-nitrobenzotrifluoride (6.18 g., 0.03 mole) is condensed with3.7 ml. (0.033 mole) of ethyl oxalyl chloride in a manner similar toexample 12, giving 6.07 g. of the title compound, m.p. 106°-110° C.,after crystallization from ethanol.

Elemental Analysis for C₁₁ H₉ F₃ N₂ O₅ : Calc'd: C, 43.1; H, 2.96; N,9.16: Found: C, 43.26; H, 2.95; N, 9.18.

EXAMPLE 38 4,4'-Oxydioxanilic acid diethyl ester. 34

The title compound is known in the literature: C.A.: 60 (P 3012b). It iscrystallized from ethanol, m.p. 159°-162° C.

EXAMPLE 39 2'-Carbamoyl-3'-methoxyoxaniclic acid cyclohexyl ester. 91

6-Amino-o-anisamide is condensed with cyclohexyl oxalyl chloride toafford the title compound, m.p. 166°-169° C.

Elemental Analysis: C₁₆ H₂₀ N₂ O₅ : Calc'd: C, 59.99; H, 6.29; N, 8.75:Found: C, 60.17; H, 6.33; N, 8.69.

EXAMPLE 40 2'-Carbamoyl-3'-methoxyoxanilic acid butyl ester. 98

6-Amino-o-anisamide is condensed with n-butyl oxalyl chloride to affordthe title compound, m.p. 126°-129° C.

Elemental Analysis for C₁₄ H₁₈ N₂ O₅ : Calc'd: C, 57.13; H, 6.17; N,9.52: Found: C, 57.43; H, 6.46; N, 9.38.

EXAMPLE 41 2'-Carbamoyl-3'-methoxyoxanilic acid sec-butyl ester. 100/70

6-Amino-o-anisamide is condensed with secondary butyl oxalyl chloride toafford the title compound, m.p. 119°-122° C.

Elemental Analysis for C₁₄ H₁₈ N₂ O₅ : Calc'd: C, 57.13; H, 6.17; N,9.52: Found: C, 56.94; H, 6.44; N, 9.50.

EXAMPLE 42 2'-Carbamoyl-3'-ethoxyoxanilic acid ethyl ester. 80

2-Amino-6-ethoxy-benzoic acid amide is condensed with ethyl oxalylchloride to afford the title compound m.p. 142°-145° C.

EXAMPLE 43 2'-Carbamoyl-3'-propoxyoxanilic acid ethyl ester. 52

2-Amino-6-propoxy-benzoic acid amide is condensed with ethyl oxalylchloride to afford the title compound, m.p. 130°-133° C.

EXAMPLE 44 2'-Carbamoyl-3'-isopropoxyoxanilic acid ethyl ester. 60

2-Amino-6-isopropoxy-benzoic acid amide is condensed with ethyloxalylchloride to afford the title compound, m.p. 123°-125° C.

EXAMPLE 45 2'-Carbamoyl-3'-n-butoxyoxanilic acid ethyl ester. 75

2-Amino-6-n-butoxy-benzoic acid amide is condensed with ethyl oxalylchloride to afford the title compound, m.p. 120°-123° C.

EXAMPLE 46 (2-Naphthyl)oxamic acid ethyl ester. 76

The title compound is known in the literature: C.A. 43:697 g., m.p.118°-120° C.

EXAMPLE 47 (1-Naphthyl)oxamic acid ethyl ester. 97

The title compound is known in the literature: C.A. 43:6973 g., m.p.105°-107° C.

EXAMPLE 48 3', 4', 5'-Trimethoxyoxanilic acid ethyl ester. 63

The title compound is known in the literature: C.S. 68:9547 y, m.p.132°-134° C.

Elemental Analysis for C₁₃ H₁₇ NO₆ : Calculated: C, 55.12; H, 6.05; N,4.95: Found: C, 55.14; H, 6.26; N, 4.87.

EXAMPLE 49 3'-Methoxy-2'-methylcarbamoyloxanilic acid ethyl ester. 72

Slow addition of 4.98 g. (0.03 mole) of 6-amino-o-anisamide to a mixtureof 57% NaH (1.32 g., 0.0315 mole) in 50 ml. dimethylformamide wascarried out at room temperature. After the evolution of H₂ ceased, themixture was cooled to 3° C. and 2.06 ml. (0.033 mole) of methyliodidewas slowly added at 3°-5° C. The temperature was allowed to go up toroom temperature and stir for 2 hours. The mixture was concentrated, theresidue extracted into ethyl acetate-water, the mixture was basified,and the ethyl acetate layer was washed with water, brine and dried.Concentration gave a tan solid that was crystallized (ethanol), giving0.45 g. (8%) Of 6-amino-N-methyl-o-anisamide m.p. 186°-189° C.

Elemental Analysis for C₉ H₁₂ N₂ O₂ : Calculated: C, 59.98; H, 6.71; N,15.55: Found: C, 60.42; H, 7.04; N, 15.42.

To a solution of 6-amino-N-methyl-o-anisamide (2.85 g., 0.0158 mole) and2.54 ml. (0.0314 mole) of pyridine in 100 ml. of CH₂ Cl₂ at 10° C., isadded 1.94 ml. (0.0174 mole) of ethyl oxalyl chloride over 5 minutes.After stirring for 2 hours at room temperature, diethyl ether is addedand washed with water and cold dilute HCl. An insoluble solid isfiltered off and crystallized from ethyl acetate-hexane, giving 0.3 g.of the title compound m.p. 119°-121° C.

Elemental Analysis for C₁₃ H₁₆ N₂ O₅ : Calculated: C, 55.71; H, 5.75; N,10.00: Found: C, 55.91; H, 6.00; N, 9.94.

EXAMPLE 50 2'-Carbamoyl-3'-(2-dimethylaminoethoxy)oxanilic acid ethylester, hydrochloride. 85

Ethyl oxalyl chloride (0.91 ml., 0.008 mole) is added to 1.81 g. (0.008mole) of 2-amino-6-dimethylaminoethoxy-benzamide at 10° C. in 100 ml. ofCH₂ Cl₂ over a period of 5 minutes. After stirring overnight, themixture is concentrated to dryness on a rotary evaporator and theresidue is triturated with diethyl ether and filtered. The solid iscrystallized from methanol, giving 1.89 g. of the title compound: m.p.209°-211° C.

Elemental Analysis for C₁₅ H₂₂ ClN₃ O₅.0.15H₂ O Calculated: C, 49.70; H,6.2; N, 11.6; Cl, 9.78: Found: C, 49.92; H, 6.66; N, 11.64; Cl, 9.85.

The 2-amino-6-dimethylaminoethoxybenzamide reactant is prepared asfollows:

To a solution of 14.06 g. (0.0728 mole) of 2,6-dinitrobenzonitrile in270 ml. of tetrahydrofuran at 40° C., a solution prepared by adding 1.67g. (0.726 mole) of sodium to 30 ml. of 2-dimethylaminoethanol is addedover 20 minutes. The solution is refluxed for 3 hours, concentrated todryness on a rotary evaporator and scrubbed three times with xylene. Theresidue is filtered with water, and crystallized from benzene-hexane,giving 7.79 g. of 2-(2-dimethylaminoethoxy)-6-nitrobenzonitrile m.p.89°-91° C.

Elemental Analysis for C₁₁ H₁₃ N₃ O₃ : Calculated: C, 56.16; H, 5.57; N,17.86: Found: C, 56.11; H, 5.70; N, 17.51.

To a solution of 7.17 g. (0.0305 mole) of2-(2-dimethylaminoethoxy)-6-nitrobenzonitrile and 3.85 ml. of 85%hydrazine hydrate in 250 ml. of absolute ethyl alcohol at 40° C. isadded small portions of Raney nickel. When the exotherm and evolution ofgases ceases, the mixture is filtered and the filtrate concentrated todryness. The residue is crystallized from ethyl acetate-hexane, giving2.13 g. of 2-amino-6-dimethylaminoethoxybenzamide: m.p. 118°-121° C.

EXAMPLE 51 2-(Ethoxycarbonylcarboxamido)-4,5-dimethylbenzoic acid. 33

To a solution of 4,5-dimethylanthranilic acid (3.30 g., 0.02 mole) and3.22 ml. (0.04 mole) of pyridine in 50 ml. of tetrahydrofuran at 10° C.,is added 2.46 ml. (0.022 mole) of ethyl oxalyl chloride over 5 minutes.After stirring for two hours at room temperature the solution isconcentrated to dryness on a rotary evaporator. The residue istriturated with water and filtered, giving 4.27 g. of the title compoundafter crystallization (ethanol): m.p. 235°-239° C.

Elemental Analysis for: C₁₃ H₁₅ NO₅ : Calculated: C, 58.86; H, 5.70; N,5.28: Found: C, 59.15; H, 5.73; N, 5.20.

EXAMPLE 52 (2-Carbamoyl-4,5-dimethylphenyl)oxamic acid ethyl ester. 100

Liquid phosgene (55 g.) is added to a stirred solution of 30.1 g. (0.182mole) of 4,5-dimethylanthranilic acid in 800 ml. of dioxane. Thetemperature is raised to 40°-45° C. and held for 2 hours, and thenstirred overnight at room temperature. The mixture is filtered and thecake washed with diethyl ether, giving 33 g. of the isatoic anhydride:m.p.>300° C. The isatoic anhydride is then added to 435 ml. of N NH₄ OH,and the mixture stirred overnight at room temperature. The mixture isrefluxed for 2 hours, cooled, filtered and crystallized (ethanol),giving 13.4 g. of 2-amino-4,5-dimethylbenzamide: m.p. 162°-7° C.

To a solution of 1.99 g. (0.0121 mole) of 2-amino-4,5-dimethylbenzamideand 1.95 ml. (0.0242 mole) of pyridine in 50 ml. of tetrahydrofuran at10° C. is added 1.49 ml. (0.0133 mole) of ethyl oxalyl chloride over 5minutes. The reaction is carried out and worked-up in a manner similarto example 51, giving 2.73 g. of the title compound aftercrystallization (ethanol), m.p. 190°-193° C.

Elemental Analysis for C₁₃ H₁₆ N₂ O₄ : Calculated: C, 59.08; H, 6.10; N,10.60: Found: C, 58.82; H, 6.31; N, 10.41.

EXAMPLE 53 2'-Acetyl-3'-methoxyoxanilic acid ethyl ester. 46

To a solution of 2-amino-6-methoxyacetophenone (2.1 g., 0.0127 mole) and2.05 ml. (0.0254 mole) of pyridine in 50 ml. of methylene chloride at10° C., is added 1.49 ml. (0.0133 mole) of ethyl oxalyl chloride over 5minutes. The reaction is carried out and worked-up in a manner similarto example 51, giving 2.06 g. of the title compound after chromatographyon acidic silica gel: m.p. 70°-73° C.

Elemental Analysis for C₁₃ H₁₅ NO₅ : Calc'd: C, 58.86; H, 5.70; N, 5.28:Found: C, 58.89; H, 5.66; N, 5.23.

EXAMPLE 54 2'-Carbamoyl-3'-(2-hydroxypropoxy)oxanilic acid ethyl ester.100

In a manner similar to example 50, but using, but using 1,2-propanediolinstead of 2-dimethylaminoethanol, one isolates a 39% yield of2-(2-hydroxy propoxy)-6-nitrobenzonitrile after crystallization(benzene): m.p. 121°-124° C.

Elemental Analysis for C₁₀ H₁₀ N₂ O₄ : Calculated: C, 54.05; H, 4.54; N,12.61: Found: C, 54.24; H, 4.64; N, 12.67.

2-Amino-6-(2-hydroxypropoxy)benzamide is produced by reducing thebenzonitrile in accordance with Example 50 in 78% yield aftercrystallization (ethyl acetate-hexane):m.p. 115°-118° C.

Elemental Analysis for C₁₀ H₁₄ N₂ O₃ : Calculated: C, 57.13: H, 6.71, N,13.33: Found: C, 57.55; H, 6.56; N, 13.33.

To a solution of 2-amino-6-(2-hydroxy propoxy)benzamide (2.05 g.,0.00976 mole) and 1.57 ml. (0.01952 mole) of pyridine in 200 ml. of CH₂Cl₂ at 10° C., is added 1.09 ml. (0.00976 mole) of ethyl oxalyl chlorideover 20 minutes. The reaction is carried out and worked-up in a mannersimilar to example 51, giving 0.18 g. of the title material afterchromatography on acidic silica gel and crystallization (ethylacetate-hexane): m.p. 131°-135° C.

Elemental Analysis for C₁₄ H₁₈ N₂ O₆ : Calculated: C, 54.19; H, 5.85; H,9.03: Found: C, 54,38; H, 6.09; N, 8.97.

EXAMPLE 55 (2-Carbamoyl-3,5-dimethoxyphenyl)oxamic acid ethyl ester.100/19 at 25 mg/kg

A solution of 1.96 g. (0.01 mole) of 4, 6-dimethoxy anthranilamide in 50ml. of methylene chloride is treated with pyridine and ethyl oxalylchloride. After 1 hour the reaction mixture is filtered and the crudeproduct is recrystallized from dimethylformamide-ethyl acetate to give2.4 g. of product, m.p. 198°-208° C.

Elemental Analysis for C₁₃ H₁₆ N₂ O₆ : Calculated: C, 52.70; H, 5.44; N,9.46: Found: C, 52.75; H, 5.56; N, 9.54.

4,6-Dimethoxyanthranilamide is prepared as follows:

A mixture of 6.7 g. (0.03) mole) of 4,6-dimethoxy isatoic anhydride and75 ml. of 1M ammonium hydroxide is stirred 16 hours at room temperature.The solid is filtered off, dried and extracted with hot ethanol. Theextracts are cooled and diethyl ether is added to give a first crop 1.2g., mp. 197°-200° C. followed by a second crop of the desired amide,m.p. 117°-119° C., 2.3 g.

Elemental Analysis for C₉ H₁₂ N₂ O₃ : Calc'd: C, 55.09; H, 6.17; N,14.28: Found: C, 55.01; H, 6.21; N, 14.12.

4,6-Dimethoxyisatoic anhydride is prepared from 4,6-dimethoxyanthranilicacid (H. Newman & R. Anzier, J. Org. Chem. 34, 3484 (1969)) and phosgeneaccording to the method of E. C. Wagner and M. F. Fegley, Org. Synthesis27, 45 (1947).

EXAMPLE 56 Oxalic acid (2-[2-aminocarbonyl-3-ethoxycarbonylcarbonylamino phenoxy]ethyl)ethyl ester. 82/26 at 10 mg/kg.

2-Amino-6-(2-hydroxyethoxy)benzamide is treated with two equivalents ofpyridine and ethyl oxalyl chloride. The usual workup gives a white solidwhich is triturated with hot ethanol and filtered to give the product,m.p. 180°-182° C.

Elemental Analysis for C₁₇ H₂₀ N₂ O₉ : Calc'd: C, 51.51; H, 5.09; N,7.07: Found: C, 51.39; H, 5.00; N, 7.11.

2-Amino-6-(2-hydroxyethoxy)benzamide is prepared by the followingprocedure:

A suspension of 6.0 g. of 2-(2-hydroxyethoxy)-6-nitrobenzonitrile on 30ml. of ethanol and 4.3 ml. of hydrazine hydrate is added slowly to asuspension of 2.9 g. of Raney nickel in 50 ml. of ethanol at such a rateto keep the temperature at 65° C. The misture is heated at reflux for1/2 hour after the addition is complete, filtered through Celite andevaporated to dryness. The solid is recrystallized from ethanol to give5.3 g. (94%) of amide, m.p. 149°-151° C.

Elemental Analysis for C₉ H₁₂ N₂ O₃ Calculated: C, 55.09; H, 6.17; N,14.28: Found: C, 54.84; H, 6.17; N, 14.27.

The 2-(2-hydroxyethoxy)-6-nitrobenzonitrile is prepared as follows:

To a solution of 19.3 g. of 2,6-dinitrobenzonitrile in 500 ml. intetrahydrofuran at reflux is added dropwise a solution of lithiumhydroxyethoxide in tetrahydrofuran prepared by adding 62.5 ml. of 1.6 Mbutyllithium in hexane to a solution of 6.2 g. of ethylene glycol in 100ml. of tetrahydrofuran at -78° C. and stirring for 1 hour. After all theethoxide is added the reaction mixture is refluxed for 4 hours, cooledand evaporated to dryness. The resulting solid is extracted with hotbenzene which yields 8.5 g. of product on cooling, m.p. 140°-142° C.

Elemental Analysis for C₉ H₈ N₂ O₄ : Calculated: C, 51.92; H, 3.87; N,13.46: Found: C, 51.98; H, 3.92; N, 13.54.

EXAMPLE 57 [2-Carbamoyl-3-(2-hydroxyethoxy)phenyl]oxamic acid ethylester 12 at 10 mg/kg per os; 49 at 30 mg/kg per os; 43 at 100 mg/kg peros.

To a suspension of 5.8 g. (30 mmole) of 2-amino-6-(2-hydroxyethoxy)benzamide in 100 ml. of dichloromethane isadded 9.48 g. (120 mmole) of pyridine followed by 6.48 g. (60 mmole) oftrimethylchlorosilane. After stirring 1 hour, 4.01 g. (30 mmole) ofethyl oxalyl chloride is added. The resulting solution is stirred for 48hours, poured into dilute hydrochloric acid and the organic phase isseparated. The aqueous layer is extracted with methylene chloride, thecombined organic layers are washed with dilute hydrochloric acid anddried and evaporated. The residue is recrystallized from ethylacetatehexane to give 7.7 g. of product, m.p. 146°-148° C.

Elemental Analysis for C₁₃ H₁₆ N₂ O₆ : Calculated: C, 52.70; H, 5.44; N,9.46: Found: C, 52.52; H, 5.42; N, 9.34.

EXAMPLE 58 3-Benzyloxy-2-carbamoylphenyl)oxamic acid ethyl ester 55/22at 25 mg/kg

2-Amino-6-benzyloxybenzamide is treated with ethyl oxalyl chloride inthe usual manner to give the ester, m.p. 151°-153° C.

Elemented Analysis for C₁₈ H₁₈ N₂ O₅ : Calculated: C, 63.15; H, 5.30; N,8.18: Found: C, 63.31; H, 5.47; N, 8.36.

2-Amino-6-benzyloxybenzamide is prepared by the Raney nickel reductionof 2-benzyloxy-6-nitrobenzonitrile (E. Cortes & F. Walls, Boll Inst.Quim. Univ. Nach. Autom. Mex. 16, 71(1964); C.A. 63, 533c(1965) in theusual manner; m.p. 158°-160° C.

Elemental Analysis for C₁₄ H₁₄ N₂ O₂ : Calculated: C, 69.40; H, 5.83; N,1.56: Found: C, 69.25; H, 6.10; N, 11.69.

EXAMPLE 59 N-Hydroxy-N'-phenyloxamide. 92

The title compound is prepared by the method of Dimroth et al., Chem.Ber. 39, 3917; m.p. 165°-167° C.

Elemental Analysis for C₈ N₈ N₂ O₃ Calculated: C, 53.33; H, 4.48; N,15.55: Found: C, 53.30; H, 4.48; N, 15.07.

EXAMPLE 60 (4-Chlorophenyl)oxamic acid ethl ester. 64

The title compound was prepared by the method disclosed in Farmaco, Ed.Sci. 22(9), 717-734 (1967); m.p. 149°-152° C.

Elemental analysis for C₁₀ H₁₀ NO₃ Cl Calculated: C, 52.76; H, 4.43; N,6.15: Found: C, 52.71; H, 4.40; N, 6.19.

EXAMPLE 61 (4-Dimethylaminophenyl)oxamic acid ethyl ester. 100/16 at 25mg/kg per os

The title compound was prepared by the method disclosed in Chem. Abstr.,72, P. 12413 M (1970); m.p. 166°-170° C.

Elemental Analysis for C₁₂ H₁₆ N₂ O₃.HCl Calculated: C, 52.84; H, 6.28;N, 10.27; Cl. 13.00: Found: C, 52.93; H, 6.28; N, 10.27; Cl, 11.98.

EXAMPLE 62 [2-(Aminocarbonyl)-3-(dimethylamino)phenyl]oxamic acid ethylester. 54/21 at 25 mg/kg per os

This is prepared from 2-amino-6-dimethylaminobenzamide and ethyl oxalylchloride in the usual manner, m.p. 133°-135° C.

Elemental analysis for C₁₃ H₁₇ N₃ O₄ Calculated: C, 55.90; H, 6.14; N,15.05: Found: C, 56.04; H, 6.21; N, 14.54

2-Amino-6-dimethylamino benzamide is prepared by the Raney nickelreduction of 2-dimethylamino-6-nitrobenzonitrile following the procedurepresented in Example 50.

2-Dimethylamino-6-nitrobenzonitrile is prepared from molar equivalentsof 2,6-dinitrobenzonitrile and dimethylamine hydrochloride indimethylformamide in the presence of aqueous KOH.

EXAMPLE 63 [2-Carbamoyl-3-(methylthio0phenyl]oxamic acid ethyl ester.98/25 at 25 mg/kg per os

This is prepared by ethyloxalation of 2-amino-6(methylthio) benzamide,m.p. 168°-170° C.

Elemental Analysis for C₁₂ H₁₄ N₂ O₄ S: Calculated: C, 51.05; H, 5.00;N, 9.92; S, 11.36: Found: C, 51.06; H, 4.92; N, 10.08; S, 11.65.

2-Amino-6-(methylthio) benzamide is prepared by Raney nickel reductionof 2-(methylthio)-6-nitrobenzonitrile which is prepared from2,6-dinitrobenzonitrile and methylmercaptan following the procedure setforth in Example 56.

EXAMPLE 64 [(2-Aminocarbonyl-3-methylsulfinylphenyl)oxamic acid ethylester 44/23 at 25 mg/kg per os

A mixture of 2.0 g. of [2-carbamyl-3-(methylthio)phenyl] oxamic acidethyl ester and 1.44 g. of m-chloroperoxybenzoic acid in 200 ml. ofmethylene chloride is stirred for 2 hours. 0.6 g. of sodium bicarbonatein 20 ml. of water is added, the methylene chloride layer is separated,dried and evaporated. The residue is recrystallized from ethanol-diethylether, m.p. 164°-166° C.

Elemental Analysis for C₁₂ H₁₄ N₂ O₅ S: Calc'd: C, 48.31; H, 4.73; N,9.39; S, 10.74: Found: C, 48,15; H, 4.56; N, 9.26; S, 10.38.

EXAMPLE 65 2'-Carbamyl-3'-methylamino-oxanilic acid 100 at from 50-100mg/kg i.p. w/decreased inhibition at 200 mg/kg and at 25 mg/kg and below

To a solution of 3.3 g. of 2-amino-6-methylaminobenzamide in 50 ml. ofTHF is added 8.0 g. of triethylamine followed by 6.5 g. oftrimethylsilylchloride. After 1 hr., 2.74 g. of ethyl oxalyl chloride in25 ml. THF is added and the mixture stirred overnight. The reactionmixture is poured into ice water and extracted with methylene chloride.The combined extracts are dried and evaporated to give a yellow oilwhich is chromatographed on silica gel two times, first with 1%methanol-chloroform and then with ethyl acetate-20% hexane. The productis recrystallized from benzene-hexane, m.p. 120°-122° C.

Elemental Analysis for C₁₂ H₁₅ N₃ O₄ : Calc'd: C, 54.33; H, 5.70; N,15.84: Found: C, 54.53; H, 5.96; N, 15.70.

The title compound is obtained by saponification and acidification bythe procedure of Example 26.

2-Amino-6-methylaminobenzamide is prepared by Raney nickel reduction of2-nitro-6-methylaminobenzonitrile as in Example 8, m.p. 130°-132°.

Elemental Analysis for C₈ H₁₁ N₃ O: Calc'd.: C, 58.16; H, 6.71; N,25.24.: Found: C, 58.01; H, 6.89; N, 25.15.

2-Nitro-6-methylaminobenzonitrile is prepared from2,6-dinitrobenzonitrile as in Example 10 using methylamine instead ofN-methylpiperazine, m.p. 203°-206°.

Elemental Analysis for C₈ H₇ N₃ O₂ : Calc'd.: C, 54.25; H, 3.99; N,23.72.: Found: C, 54.24; H, 3.70; N, 24.02.

What is claimed is:
 1. A compound of the formula: ##STR6## wherein R¹ isamino or lower(alkyl)amino;R² in N-mono- or di-loweralkylamino(lower)alkoxy or mono- or di-lower alkylamino; R³ is hydrogen,lower alkyl, lower alkoxy, halo or nitro; R⁴ is hydrogen, lower alkyl orlower alkoxy;or a pharmaceutically acceptable salt thereof.
 2. Acompound of claim 1 in which R¹ is --NH₂.
 3. A compound of claim 2 inwhich R² is lower alkylamino.
 4. A compound of claim 2 in which R² isdi(lower)alkylamino.
 5. A compound of claim 2 which is2'-carbamyl-3'-(2-dimethylaminoethoxy)oxanilic acid or apharmaceutically acceptable salt thereof.
 6. A compound of claim 4 whichis 2'-carbamyl-3'-dimethylamino-oxanilic acid or a pharmaceuticallyacceptable salt thereof.
 7. A compound of claim 3 which is2'-carbamyl-3'-methylamino-oxanilic acid or a pharmaceuticallyacceptable salt thereof.